Abstract
Muscle atrophy and skeletal muscle fibrosis are significant pathological manifestations of primary sarcopenia. The regulation of C2C12 myoblast and skeletal muscle fibroblast apoptosis is associated with these pathological changes. Previous studies have indicated that irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), can alleviate primary sarcopenia. However, the mechanisms of the effect of irisin in age-related apoptosis remain unknown. Our present research aimed to explore the effect of irisin and the underlying mechanism of d-galactose (d-gal)-induced apoptosis in skeletal muscle fibroblasts and C2C12 myoblasts. We found the opposite effects of d-gal on C2C12 myoblasts and fibroblasts. We also found that irisin suppressed C2C12 cell apoptosis and promoted fibroblast apoptosis. Mechanistically, irisin altered d-gal-induced apoptosis by increasing caveolin-1 expression. Taken together, these findings further demonstrated that irisin is a potential agent that can treat aged-relative muscle atrophy and fibrosis.
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on request.
References
Wiedmer P, Jung T, Castro JP et al (2021) Sarcopenia – molecular mechanisms and open questions. Ageing Res Rev 65:101200. https://doi.org/10.1016/j.arr.2020.101200
Larsson L, Degens H, Li M et al (2019) Sarcopenia: aging-related loss of muscle mass and function. Physiol Rev 99:427–511. https://doi.org/10.1152/physrev.00061.2017
Tieland M, Trouwborst I, Clark BC (2018) Skeletal muscle performance and ageing. J Cachexia Sarcopenia Muscle 9:3–19. https://doi.org/10.1002/jcsm.12238
Cheema N, Herbst A, Mckenzie D, Aiken JM (2015) Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities. Aging Cell 14:1085–1093. https://doi.org/10.1111/acel.12399
Zhiyin L, Jinliang C, Qiunan C et al (2021) Fucoxanthin rescues dexamethasone induced C2C12 myotubes atrophy. Biomed Pharmacother 139:111590. https://doi.org/10.1016/j.biopha.2021.111590
Wang D, Song M, Shen LF et al (2022) Exercise capacity is improved by levosimendan in heart failure and sarcopenia via alleviation of apoptosis of skeletal muscle. Front Physiol 12:1–14. https://doi.org/10.3389/fphys.2021.786895
Boström P, Wu J, Jedrychowski MP et al (2012) A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–468. https://doi.org/10.1038/nature10777
Schumacher MA, Chinnam N, Ohashi T et al (2013) The structure of Irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation. J Biol Chem 288:33738–33744. https://doi.org/10.1074/jbc.M113.516641
Storlino G, Colaianni G, Sanesi L et al (2020) Irisin prevents disuse-induced osteocyte apoptosis. J Bone Miner Res 35:766–775. https://doi.org/10.1002/jbmr.3944
Yano N, Zhang L, Wei D et al (2020) Irisin counteracts high glucose and fatty acid-induced cytotoxicity by preserving the AMPK-insulin receptor signaling axis in C2C12 myoblasts. Am J Physiol - Endocrinol Metab 318:E791–E805. https://doi.org/10.1152/AJPENDO.00219.2019
Alsaawi TA, Aldisi D, Abulmeaty MMA et al (2022) Screening for sarcopenia among elderly arab females: influence of body composition, lifestyle, irisin, and vitamin D. Nutrients 14:1–12. https://doi.org/10.3390/nu14091855
Guo M, Yao J, Li J et al (2023) Irisin ameliorates age-associated sarcopenia and metabolic dysfunction. J Cachexia Sarcopenia Muscle 14:391–405. https://doi.org/10.1002/jcsm.13141
Wu Y, Wu Y, Yu J et al (2023) Irisin ameliorates d-galactose-induced skeletal muscle fibrosis via the PI3K/Akt pathway. Eur J Pharmacol 939:175476. https://doi.org/10.1016/j.ejphar.2022.175476
Gvaramia D, Blaauboer ME, Hanemaaijer R, Everts V (2013) Role of caveolin-1 in fibrotic diseases. Matrix Biol 32:307–315. https://doi.org/10.1016/j.matbio.2013.03.005
Sun X, Ji G, Li P et al (2021) miR-344-5p modulates cholesterol-induced β-cell apoptosis and dysfunction through regulating caveolin-1 expression. Front Endocrinol (Lausanne) 12:1–13. https://doi.org/10.3389/fendo.2021.695164
Lin F, Pei L, Zhang Q et al (2018) Ox-LDL induces endothelial cell apoptosis and macrophage migration by regulating caveolin-1 phosphorylation. J Cell Physiol 233:6683–6692. https://doi.org/10.1002/jcp.26468
Shihata WA, Putra MRA, Chin-Dusting JPF (2017) Is there a potential therapeutic role for caveolin-1 in fibrosis? Front Pharmacol 8:1–8. https://doi.org/10.3389/fphar.2017.00567
Chen QN, Fan Z, Lyu AK et al (2020) Effect of sarcolipin-mediated cell transdifferentiation in sarcopenia- associated skeletal muscle fibrosis. Exp Cell Res. https://doi.org/10.1016/j.yexcr.2020.111890
Dupont-Versteegden EE (2005) Apoptosis in muscle atrophy: relevance to sarcopenia. Exp Gerontol 40:473–481. https://doi.org/10.1016/j.exger.2005.04.003
Wu Y, Wu Y, Yang Y et al (2022) Lysyl oxidase-like 2 inhibitor rescues d-galactose-induced skeletal muscle fibrosis. Aging Cell. https://doi.org/10.1111/acel.13659
Kasper M, Barth K (2009) Bleomycin and its role in inducing apoptosis and senescence in lung cells - modulating effects of caveolin-1. Curr Cancer Drug Targets 9:341–353. https://doi.org/10.2174/156800909788166501
Sheikh MS, Fornace AJ (2000) Death and decoy receptors and p53-mediated apoptosis. Leukemia 14:1509–1513. https://doi.org/10.1038/sj.leu.2401865
Dirks A, Leeuwenburgh C (2002) Apoptosis in skeletal muscle with aging. Am J Physiol - Regul Integr Comp Physiol 282:519–527. https://doi.org/10.1152/ajpregu.00458.2001
Dhillon RJS, Hasni S (2017) Pathogenesis and management of sarcopenia. Clin Geriatr Med 33:17–26. https://doi.org/10.1016/j.cger.2016.08.002
Shang GK, Han L, Wang ZH et al (2020) Sarcopenia is attenuated by TRB3 knockout in aging mice via the alleviation of atrophy and fibrosis of skeletal muscles. J Cachexia Sarcopenia Muscle 11:1104–1120. https://doi.org/10.1002/jcsm.12560
Chen C, Yang JS, Lu CC et al (2020) Effect of quercetin on dexamethasone-induced C2C12 skeletal muscle cell injury. Molecules 25:1–16. https://doi.org/10.3390/molecules25143267
Chen L, Chen L, Wan L et al (2019) Matrine improves skeletal muscle atrophy by inhibiting E3 ubiquitin ligases and activating the Akt/mTOR/FoxO3α signaling pathway in C2C12 myotubes and mice. Oncol Rep 42:479–494. https://doi.org/10.3892/or.2019.7205
Hecker L, Logsdon NJ, Kurundkar D et al (2015) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Trans Med. https://doi.org/10.1126/scitranslmed.3008182
Baar MP, Brandt RMC, Putavet DA et al (2017) Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169:132-147.e16. https://doi.org/10.1016/j.cell.2017.02.031
Mukund K, Subramaniam S (2020) Skeletal muscle: a review of molecular structure and function, in health and disease. Wiley Interdiscip Rev Syst Biol Med 12:1–46. https://doi.org/10.1002/wsbm.1462
Plikus MV, Wang X, Sinha S et al (2021) Fibroblasts: origins, definitions, and functions in health and disease. Cell 184:3852–3872
Huang Q, Zhong W, Hu Z, Tang X (2018) A review of the role of cav-1 in neuropathology and neural recovery after ischemic stroke. J Neuroinflammation 15:1–16. https://doi.org/10.1186/s12974-018-1387-y
Jin KR, Yun JC, Ryoo BY et al (2007) p53 enhances gefitinib-induced growth inhibition and apoptosis by regulation of Fas in non-small cell lung cancer. Cancer Res 67:1163–1169. https://doi.org/10.1158/0008-5472.CAN-06-2037
Hinz B, Lagares D (2020) Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat Rev Rheumatol 16:11–31. https://doi.org/10.1038/s41584-019-0324-5
Funding
This work was financially supported by funding from the National Natural Science Foundation of China (No. 81901424) and the Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0327).
Author information
Authors and Affiliations
Contributions
Conceptualization, Y.W., Y.W. and K.Z.; Data curation, Y.W., Y.W. and J.Y.; Formal analysis, Y.W. and Y.Z; Funding acquisition, J.C. and Y.S.; Investigation, X.D.; Methodology, J.Y.; Project administration, Q.X.; Software, Y.W.; validation, K.Z. and Y.Y.; Supervision, K.Z. and Y.Y.; Visualization, Y.W.; Writing—original draft, Y.W.; Writing—review and editing, Y.W. All authors have read and agreed to the published version of the manuscript. Figure 6 was illustrated using BioRender.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Wu, Y., Wu, Y., Yu, J. et al. Irisin alters d-galactose-induced apoptosis by increasing caveolin-1 expression in C2C12 myoblasts and skeletal muscle fibroblasts. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04990-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11010-024-04990-6